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Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Thyroid cancer has a higher incidence in women than in men, and it has been hypothesized that hormonal factors may explain such disparity. We performed a meta-analysis of observational prospective studies to investigate the association between menstrual and reproductive variables and exogenous hormone use and the risk of thyroid cancer among women., Methods: We calculated summary relative risks and 95% confidence intervals (95% CI) using random effect models., Results: Overall, 5,434 thyroid cancer cases from twenty-four papers were included. Increasing age at first pregnancy/birth (SRR 1.56, 95% CI 1.01-2.42) and hysterectomy (SRR 1.43, 95% CI 1.15-1.78) were associated with thyroid cancer risk. Women that were in menopause at enrolment had a reduced thyroid cancer risk (SRR 0.79, 95% CI 0.62-1.01). No other menstrual, reproductive, and hormonal variable was associated with thyroid cancer risk., Conclusions: Menstrual and reproductive factors may play a role in the etiology of thyroid cancer, possibly through the mediation of estrogen receptors.

Purpose of Review: The incidence of differentiated thyroid cancer (DTC), especially among small tumors, is increasing worldwide, despite the fact that the mortality rate from thyroid cancer remains stable. Total thyroidectomy with or without radioiodine therapy is actually the standard treatment. In the last 2 decades, several studies have shown that lobectomy could be an alternative to total thyroidectomy in low-risk DTC without compromising overall survival. The aim of this article was to assess the role of conservative surgery (hemithyroidectomy) in DTC reviewing the literature data., Recent Findings: Recent advances in diagnostic techniques allow treatment to be tailored to patients' needs. The latest consensus guidelines suggest that patients with high-risk tumors should undergo total thyroidectomy, whereas patients with small, low-risk, node-negative DTC may be candidates for conservative surgery. Careful risk evaluation and stratification makes it possible to individualize treatment, avoid overtreatment and guarantee a good long-term prognosis with low recurrence risk. Excellent prognosis of DTC would require large sample sizes and long-term follow-up for prospective trials comparing the outcomes of total thyroidectomy vs. lobectomy; however, there are several remarkable retrospective studies., Summary: Based on current clinical data, a conservative surgery might be appropriate for patients with low-risk DTC.

The purpose of this study is to determine if there are differences in the expression of estrogen-regulated genes (ERGs), proliferation-associated genes and the progesterone effector RANKL, in premenopausal ER+ breast cancer as a result of the major changes in hormone levels that occur through the menstrual cycle. Primary ER+ tumours from 174 patients were assigned to one of three menstrual cycle windows: W1 (days 27-35 + 1-6), W2 (days 7-16) and W3 (days 17-26). RNA expression of 42 genes, including 24 putative genes associated with plasma E2 levels, seven proliferation genes and RANKL was measured. Expression of PGR, TFF1, GREB1 and PDZK1 followed the previously reported pattern: a higher level in W2 compared to W1 while W3 had an intermediate value, mirroring changes in plasma estradiol. Of the other 20 ERGs, four (RUNX1, AGR2, SERPINA3 and SERPINA5) showed significant differences (p = 0.009-0.049) in expression across the menstrual cycle. The expression of six of seven proliferation-associated genes varied across the cycle but differently from the ERGs, being 20-35 % lower in W3 compared to W1 and W2 (p = 0.004-0.031). Expression of RANKL was 2.5 to 3-fold highest in W3 (p = 0.0001) and negatively correlated to the expression of the proliferation-associated genes (r = -0.37; p < 0.0001). Expression of proliferation-associated genes and RANKL in ER+ breast tumours varies across the menstrual cycle showing a different rhythm to that of ERGs. This may affect the interpretation of gene expression profiles but may be exploitable as an endogenous test of endocrine responsiveness.

Differentiated thyroid cancers may be associated with regional lymph node metastases in 20-50% of cases. The central compartment (VIupper VII levels) is considered to be the first echelon of nodal metastases in all differentiated thyroid carcinomas. The indication for central neck dissection is still debated especially in patients with cN0 disease. For some authors, central neck dissection is recommended for lymph nodes that are suspect preoperatively (either clinically or with ultrasound) and/or for lymph node metastases detected intra-operatively with a positive frozen section. In need of a better definition, we divided the dissection in four different areas to map localization of metastases. In this study, we present the rationale for central neck dissection in the management of differentiated thyroid carcinoma, providing some anatomical reflections on surgical technique, oncological considerations and analysis of complications. Central neck dissection may be limited to the compartments that describe a predictable territory of regional recurrences in order to reduce associated morbidities.

Plasma estradiol (E2) and progesterone vary markedly through the menstrual cycle. Data on whether these differences in hormone levels affect gene expression in oestrogen receptor-positive (ER+) tumours are inconsistent. We wished to determine whether there are substantial changes in the expression of oestrogen-regulated genes (ERGs) in ER+ breast cancer through the menstrual cycle. One hundred and seventy five paraffin-embedded ER+ breast carcinomas from premenopausal patients were analysed. Timing of the ovarian cycle was confirmed using serum progesterone levels. Patients were ascribed to one of three pre-defined menstrual cycle windows: 1 (days 27-35 + 1-6), 2 (days 7-16) and 3 (days 17-26). The RNA expression of ESR1, four ERGs (PGR, GREB1, TFF1 and PDZK1), and three proliferation genes (MKI67, TOP2A and CDC20) were compared between the windows. Gene expression of the four ERGs was 53-129 % higher in window 2 than window 1 (p = 0.0013, 0.0006, 0.022 and 0.066 for PGR, GREB1, TFF1 and PDZK1, respectively) and lower (9-41 %) in window 3 compared to window 2 (p = 0.079, 0.31, 0.031 and 0.065 for PGR, GREB1, TFF1 and PDZK1, respectively). Their average expression (AvERG) was 64 % higher in window 2 than window 1 (p < 0.0001) and 21 % lower in window 3 than window 2 (p = 0.0043). There were no significant differences between the windows for ESR1 and proliferation genes. In agreement with the gene expression data, progesterone receptor protein levels measured by immunohistochemistry (IHC) were 164 and 227 % higher in windows 2 and 3, respectively, compared to window 1 (30.7 and 37.9 % cells positive vs. 11.6 %; p = 0.0003 and 0.0004, respectively), while no difference in ER IHC score was observed. In conclusion, we observed significant differences in the expression of ERGs in ER+ breast tumours across the menstrual cycle. This variability may affect the interpretation of gene expression profiles incorporating ERGs and may be exploitable as an endogenous test of endocrine responsiveness.

The evolution of new techniques for cancer surgery has led to important changes in cancer care in recent years. The endpoint of cancer treatment is now to treat the patient with minimum discomfort while respecting quality of life. New techniques, such as mini-invasive surgery, must respect the correct oncological indications, when technically feasible. The surgery for nodal spread or recurrence of disease, after previous surgery on T or T and N for neck cancer, can represent a diagnostic and therapeutic challenge, especially in the neck, which is characterized by small spaces and noble structures. Often lesions become enveloped in scar tissue and can be difficult to visualize during surgery, representing a genuine problem for the surgeon. Ultrasound dye-assisted surgery is a procedure that combines ultra-sound localization of pathological nodes with the use of methylene blue to mark diseased structures to simplify their visualization (and thus removal) in the surgical field. The technique is simple and can be used in surgically and oncologically experienced hands, even in hospitals that do not have sophisticated technology.

Some medical definitions remain the same for many years, others change due to the progress in the diagnostic tools, which are able to distinguish markers and symptoms until then undetectable. Occult thyroid carcinoma is a general term indicating clinically different situations, whereas the incidentally detected papillary thyroid microcarcinoma is the most important from the clinical point of view. It is fundamental, for therapeutic management, to determine biological parameters which would define a small group of papillary thyroid microcarcinomas with aggressive biological behaviour. The most promising genetic and molecular markers for papillary thyroid carcinoma risk stratification are discussed in this review. Preoperative evaluation of these markers, obtained through analysis of ultrasonography-guided fine needle biopsy specimens of papillary thyroid microcarcinoma, could be very valuable in guiding treatment of this type of cancer.

The thyroid gland has long since been known for its self-renewal ability, mainly in cases of hyperplastic disease such as goitre. Recently the amazing improvement in knowledge about stem cells has explained this potentiality. Some stem cell features and their clinical usefulness are summarized here, reviewing data from the literature: (1) the proven presence of adult stem cells in thyroid tissue, either normal, goitrous or neoplastic, bring with it important implications regarding tissue regeneration and oncogenesis; (2) modifying culture conditions and micro-environment stem cells have led to mature tissue with specialized functions. This has considerably changed the attitude of regenerative medicine and cancer research; (3) finally, identification of stem cells and stem cell markers in thyroid cancer, gives hope for the development of new therapeutic approaches in recurrent or treatment-resistant thyroid cancer.

Thyroid cancer is the most common endocrine malignancy, more frequently diagnosed in young women during childbearing age and approximately 10% of all thyroid cancers are diagnosed during pregnancy or in the early post-partum period. Thyroid cancer in young people has generally an excellent prognosis, and survival among women with thyroid cancer diagnosed during pregnancy may not differ from that in age-matched non-pregnant women with similar cancer. Pregnancy after treatment of thyroid carcinoma requires both maternal and foetal controls. Of utmost importance is to ensure adequate maintenance of maternal levels of levothyroxine, needed by both the foetal central nervous system for its normal maturation and the mother to avoid possible recurrence or spread of the disease. In the present investigation, to confirm normal foetal growth and foetal thyroid development, an ultrasound study of the foetal thyroid was performed in 40 full term pregnancies in 32 women receiving levothyroxine treatment for previously treated thyroid cancer. In patients undergoing either suppressive or substitutive levothyroxine treatment, foetal thyroid growth was noted to be normal in all the cases, newborn thyroid status was always normal, and the incidence of maternal morbidity was not influenced. In the present study group, pregnancy does not appear to compromise mother's disease-free interval, nor to be compromised by thyroid cancer treatment. Results of the present study confirm that regular adjustment of levothyroxine treatment is of utmost importance for both maternal and foetal well-being and that foetal thyroid ultrasound study may add useful and reassuring data about child well-being.

The aim of curative surgical oncology is to remove the primary tumour with a wide margin of normal tissue. What constitutes a sufficiently wide margin particularly in oral cancer is fundamentally unclear. The currently accepted standard is to remove the primary lesion with a 1.5-2 cm circumferential macroscopic margin. In the last ten years, anatomical considerations in the approach to primary, advanced and untreated tumours of the tongue led us to develop and improve a new surgical approach to their demolition and reconstruction. From July 1999 to July 2009, at the European Institute of Oncology in Milano, Italy, 155 patients were treated, while defining and refining the concept of compartmental tongue surgery (CTS) and its main components: 1) anatomical approach to the disease that requires removal of the primary lesion and all of the potential pathways of progression--muscular, lymphatic and vascular; 2) identification of a distinct territory at risk of metastatic representation of the disease: the parenchymal structures between the primary tumour and the cervical lymphatic chain that include the muscular (mylohyoid), neuro-vascular (lingual nerve and vein) and glandular (sublingual and submandibular) tissues; 3) preparation for a rational reconstruction in consideration of a functional defect resulting from this anatomical demolition.

Prophylactic central neck dissection in papillary thyroid cancer is controversial. In this retrospective cohort study, the aim was to assess possible advantages of prophylactic central neck dissection with total thyroidectomy in cN0 papillary thyroid cancer. A total of 244 consecutive patients with papillary thyroid cancer, without clinical and ultrasound nodal metastases (cN0), were evaluated out of 1373 patients operated for a thyroid disease at the Istituto Europeo di Oncologia, Milan, Italy from 1994 to 2006. Of these 244 patients, 126 (Group A) underwent thyroidectomy with central neck dissection, while 118 (Group B) underwent thyroidectomy alone. Demographic, clinical and pathological features were analysed. Overall recurrence rate was 6.3% (8/126) in Group A and 7.7% (9/118) in Group B, with a mean follow-up of 47 (Group A) and 64 (Group B) months. In Group A patients, 47% were pN1a and all patients with recurrence had nodal involvement (p = 0.002). Survival rate did not differ in the two groups. Nine patients were lost to follow-up. Group A patients were older and their tumours were larger in size; according to the pT distribution, a higher extra-capsular invasion rate was observed. The two groups were equivalent as far as concerns histological high risk variants and multifocality. Nodal metastases correlated with stage: pT1-2 vs. pT3-T4a, p = 0.0036. A lower risk of nodal metastases was related to thyroiditis (p = 0.0034). In conclusion, central neck metastases were predictive of recurrence without influencing prognosis. From data obtained, possible greatest efficacy of central neck dissection in pT3-4 papillary thyroid cancer without thyroiditis is suggested.

Telemedicine is extremely useful when distance could hinder diagnostic procedures, disease management, or when severe side-effects may occur in patients not within easy reach of medical care and requiring prompt action and specific therapies. Telemedicine has been successfully adopted in the management of chronic patients, particularly in those with cardiologic or oncologic diseases. In the treatment of differentiated thyroid cancer, requiring long-term check-ups and visits as well as administration of high doses of levothyroxine (TSH - thyroid-stimulating hormone - suppression), also in elderly patients, telemedicine seems particularly indicated. Moreover, these distant monitoring techniques could not only reduce long-term management costs but also considerably decrease cardiovascular risks associated with these patients. The present review aims to provide some general information on telemedicine and its possible fields of action with regard to distant monitoring of patients with differentiated thyroid carcinoma.

Thyroid cancer is the most common endocrine neoplasm; however, it only accounts for less than 1% of all human malignances. Thyroid cancers are divided into well differentiated and non-well differentiated cancers, according to their histology and behavior. The surgical management options of well-differentiated thyroid cancer include total or near-total thyroidectomy, subtotal thyroidectomy and lobectomy plus isthmusectomy. The extent of surgery for thyroid cancer continues to be an area of controversy. Complications associated with thyroid surgery are directly proportional to the extent of thyroidectomy and inversely proportional to the experience of the operating surgeon. They occur less frequently with good surgical technique and better understanding of surgical anatomy, and include wound healing and infections (seroma, hematoma and wound infection), nerve injury, hypoparathyroidism, hypothyroidism, postoperative hemorrhage and respiratory obstruction.

Thyroglobulin is considered a reliable marker of recurrent disease in patients with well-differentiated thyroid carcinoma. However, some patients present recurrence with no increase in serum thyroglobulin. In the attempt to identify patients who might present recurrence with no such sign of the disease, thyroglobulin levels have been determined pre-operatively in 185 consecutive patients scheduled for primary treatment for well-differentiated thyroid carcinoma from June 1997 to May 2002 at the Head and Neck Division of the European Institute of Oncology. In 22 patients (11.9% of total), serum thyroglobulin was undetectable. In none of these 22 cases was thyroglobulin detected during follow-up, either during thyroxin suppressive therapy or during withdrawal for radioiodine scan. One of these low-thyroglobulin patients developed recurrent disease involving cervical lymph nodes, with positive radioiodine scan: thyroglobulin remained undetectable. On the contrary, in the patients with high or normal thyroglobulin presenting recurrence, the recurrence was indicated, in all cases, by increased thyroglobulin levels. From these findings it may be concluded that pre-operative assessment of serum thyroglobulin may identify patients who might present recurrence without increased thyroglobulin, and in whom standard follow-up by monitoring thyroglobulin serum levels is inadequate.

Despite their specific functional consequences, radiotherapy-induced thyroid abnormalities remain under-estimated and underreported. These sequelae may include primary or central hypothyroidism, thyroiditis, Graves' disease, euthyroid Graves' ophthalmopathy, benign adenomas, multinodular goitre and radiation-induced thyroid carcinoma. Primary hypothyroidism, the most common radiation-induced thyroid dysfunction, affects 20-30% of patients administered following curative radiotherapy to the neck region, with approximately half of the events occurring within the first 5 years after therapy. The relative risk of radiation-induced cancer (mainly well-differentiated tumours) is 15-53-fold higher than in non-irradiated population. The aetiology of radiation-induced thyroid injury includes vascular damage, parenchymal cell damage and auto-immune reactions. Total radiotherapy dose, irradiated volume of the thyroid gland, and the extent of prior thyroid resection are among the most important factors associated with the risk of hypothyroidism. The contribution of other treatment modalities (chemotherapy, endocrine therapy) as well as patient- and tumour-related factors is less clear. Reduction in radiation dose to the thyroid gland and hypothalamic/pituitary complex should be attempted whenever possible. New radiotherapy techniques, such as stereotactic radiosurgery, three-dimensional conformal irradiation, intensity modulated radiotherapy and proton therapy allow generally better dose distribution with lower dose to the non-target organs. The diagnostic approach to thyroid radiation injury includes baseline thyroid function assays in all patients undergoing thyroid or parasellar irradiation. Recommended follow-up procedures include at least annual evaluation with a history for symptoms of thyroid dysfunction, clinical examination, and measurement of thyroid hormones and thyrotropin. Management of overt hypothyroidism is based on hormone replacement therapy. Thyroid hormone therapy is also recommended in cases of subclinical hypothyroidism. Treatment of other radiation-induced thyroid disorders (thyroiditis, Graves' disease, thyroid cancer) is similar to that employed in spontaneously occurring conditions. Further improvements in radiotherapy techniques and progress in endocrine diagnostics and therapy may allow better prevention and management of radiation-related thyroid injury.